Bibenzothiazoles and method for producing the same



UNITED STATES PATENT OFFICE BIBENZOTHIAZOLES AND METHOD FOR PRODUCING THE SAME Norbert Steiger, Nutley, N. J assignor to Hall'- mann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application April 16, 1952, Serial No. 282,680

11 Claims. (Cl. 260306.6)

This invention relates to bibenzothiazoles and The 2,2'-bis(mercapto)-4,4-bis(hydroxy)-6,6-

more particularly to 2,2'-bis(di-lower alkylaminobibenzothiazole employed as an intermediate is,

alkylmercapto)-4,4'-bis(,B-di-lower alkylaminoto my best knowledge, new and can be readily alkoxy) -6,6-bibenzothiazoles and the acid addiprepared as illustrated by the following example: tion salts thereof.

The compounds in the form of the free base ExampleA can be represented by the following formula: 160 am of i th ybenzidine dihydrochloride, 450 cc. of sulfur monochloride, and 150 1 cc. of acetic acid were heated within 1 hour to R0 100 C. then to 108-110 C. for 6 hours. The reaction'product was filtered at 50 0., washed with benzene, and sucked dry. The formed 4,4-dimetl1oxy-6,6'-bis(benzo-2,3-thiaza 1 thionium I chloride was added with agitation to a solution made up of 600 cc. of alcohol, 550 cc. of sodium hydroxide (40%), 25 grams of sodium hydrosul- RO- s fite, and 25 grams of sodium sulfide. The tem- (L perature roseto 65 C. 300 cc. of water and 10 N: -SR grams of sodium hydrosulfite Were added; and the wherein R stands for di-lower alkylaminoalkyl. reaction mixturiwas heated one'half at The invention also embraces the method for Then a solution of 100 cc. of carbon disulfide producing the aforesaid compounds and novel In 9 of alcohol was Slowly added and the intermediates employed in their production. The

2,2'bis(di-lower alkylaminoalkylmercapto) -4,4'- bis fi alkylalminoalkoxy) r were distilled 01T- TO the resldue Was added thiazoles are trichomonacides. a of sodium f f The Sodium i 9 In general, the novel compounds can be pre- 3 -.bls(methoxy) pared by reacting 22, bis (mercapto) 4,4, bis benzothiazole thus obtained was filtered at room hydroxy)-6,6'-bibenzothiazole in the form of its tempferature Washed .With 20% .sodium alkali metal Salt, as, for example, the sodium, chloridesolution. The sodium salt Was dissolved in hot water (90 C.) filtered, and the filtrate was acidified with hydrogen chloride, whereupon 2,2- bis(mercapto) -4,4'-bis(methoxy) -6,6 bibenzothiazole precipitated. It was filtered off and dried.

alkylaminoalkyl halide, as, for example, l-dimethylamino-Z-chloro-ethane, l-di-ethylaminoz-chloro-ethane, 2-chloro-1-diethylamino propane, and the like. The reaction is preferably carried out in the presence of an organic solvent T bl.s(mercapto) bls (methoxwf or diluent, as, for example, chlorobenzene, tol- -blbenzothlazole, hydrolyzed uene, xylene, and the like. The 2,2'-bis(di-lower bmmereaptol blsfhydroxy) alkylaminoalkylmercapto) -4,4bis( 3 di lower benzothlazole m w manner: alkylaminoalkoxy) -6,6-bibenzothiazo1es can be 0 40 grams of bwupercapm) recovered from the reaction medium as the free gen chloride or hydrogen bromide into the reacaction mass was then cooled to 200 and 100 tion m dium. T f 88 grams of ice and 100 cc. of water were added 8 he r bases readfly yleld acld and stirred for 1 hour. The chlorobenzene was acids. Thus, by treating the bases with an equivliemoved from the reafztion mixture by steam alent amount f an amd as, for example, hydro tillation To the residue were added 25 cc of chloride, hydrobromjc sulfuric phosphoric, concentrated hydrochloric acid (specify gravity tric, acetic, propionic, caprylic, undecylenic, tar- 119) and 500 of r, and the mixture a taric and citric acids, the corresponding acid adfiltered. The residue, which, after drying, was dition salts of 2.2'-bis(di-lower alkylaminoalkylobtained as a sandy powder of slight tan color,

mercapto) 4,4 bisQB-di-lower alklyaminoalkwas 2,2 bis(mercapto) 4,4 bis(hydroxy)- oxy) -6,6'-bibenzothiazoles are obtained. 6.6'-bibenzothiazole.

The following examples will serve to illustrate the preparation of the 2,2-bis(di-lower alkylaminoalkylmercapto) -4,4-bis(B-di-lower alkylaminoalkoxy) -6,6 -bibenzothiazoles:

Example 1 18 grams of 2,'2'-bis(mercapto)-4,4'-bis(hydroxy) -6,6-bibenzothiazole, 300 cc. of chlorobenzene, 12 gram of sodium methylate, and 35 cc. of methanol were heated together with agitation to 70 C. for one-half hour then heated within 1 hour to 130-133 C. to allow the "methanol to distill off completely. The reaction mess comprising 2,2 bis(mercapt) 4,4 bis(hydroxy)-6,6'bibenzothiazole sodium salt was cooled to 90 C. and 30 grams of l-diethylamino- 2-chloro-ethane were added. The reaction mikture was heated to 130133 C. for 4 hours with stirring and under reflux. The reaction mass was then permitted to cool to 100 C. and 150 cc. of water and '10 cc. of sodium hydroxide solution were added, the mixture stirred for one-half hour, and the chlorobenzene layer which contained the reaction product was separated from the aqueous layer in a separatory funnel. The chlorobenzene solution was then dried over sodium sulfate and filtered. To the filtrate, comprising 2.2- bis f3 diethylaminoethylmercapto) 4,4 b's- (,8 diethylaminoethoxy) 6,6 bibenzothiazole, were added 50 cc. of a 30% methanol-hydrogen chloride solution, whereupon 2,2 bis- (5 diethylaminoethylmercapto) 4,4 -bis- (5 diethylaminoethoxy) -'6,6 bibenzothiazole tetrahydrochloride precipitated 'as a cream-colored sandy powder. Recrystallized from methanol-ether, the tetrahydrochloride melted=at 230 C., with decomposition. The compound is very soluble in water. methanol, and ethanol.

9 grams of the tetrahydroc'hloride were dissolved in 100cc. of water. To the resulting solution were added in a separatory funnel 100 cc. of ether and 8 cc. of 40% sodium hydroxide-solution. The ether solution of the base thus formed was concentrated. The concentrate was 'dissolved in alcohol and filtered. To the filtrate were added 4.5 grams of lactic acid in 10- ccxof alcohol. The alcohol was '-removed in vacuo. The 2,2 -bis (5-diethylaminoethylmercapto)- -4,4 bis p diethylaminoethoiry)=6,6=bibenzothiazole lactate was then obtained as asyr-upy oil which was very soluble in water.

Example 2 '72 grams of 2,2-bis(mercapto) -4,4--bis( hy droxy) -6,6-bibenzothiazole, 48 grams of sodium methylate, 900 cc. of chlorobenzene, and 120 cc. of methanol were heated together with agitation to 70 C. for one-half hour, then heated within 1 hour to 130-133;C. to-allow the methanol to distill off completely. After cooling the reaction mass to 90 C., 500 cc. of a chlorobenzene solution containing 120 grams of l-dimethylamino- 2-chloro-ethane were added, and the reaction mass was heated to the boilunderreflux andgood agitation for 4 hours. After cooling to C., 500 cc. of water and 25 cc.-of 40% sodium hydroxide solution were added and the mixture heated to 70 C. forlhour. The chlorobenzene layer which contained the reaction product was separated from the aqueous layer in a separatory funnel. The chlorobenzene solution was dried over sodium sulfate and filtered. The filtrate comprising 2,2 bis(B-diinethylaminoethylrnercapto) 4,4 bisqi dimethylaminomethoxy)- 6,6-bibenzothiazole, was diluted with 1,000 cc. of

aeetone. To the resulting solution were added 115 cc. of a 35% methanol-hydrogen chloride solution. The 2,2 bisUi-dimethylaminoethylmercapto) 4,4 bis(B-dimethylaminomethoxy) 6,6-bibenzothiazole tetrahydrochloride precipitated in the form of cream colored'crystals. The compound was filtered off and washed with acetone. It was recrystallized from methanolacetone, M. P. 223 C. The tetrahydrochloride is very soluble in water, soluble in methanol, ethanol, and isopr'opanol.

Example 3 1's grams or '2,"2-bis(mercapto)-4,4'-bis(hydrexy)-6,6 bibenzothiazole, 300 cc. of chlorobenzene, 12 grams of sodium methylate, and 35 cc. of rne't'ha'n'ol were heated with agitation to 70 C. for one-half hour and then heated within 1 hour to 130-133 C. to allow the methanol to distill oil completely. After cooling to C., 32 grams of 1 dimethylamino-2-chloro propane were added and the reaction mixture was heated under refiux with agitation for 4 hours at 130 133 C. The reaction mass was then permitted to coolto C.,and 200 cc. of water and 5 cc. of a 40% sodium hydroxide solution were added. The mixture was stirred 'for 1 hour and 'the chlorobe'nzene layer which contained the reaction product was separated from the aqueous layer in a separatory funnel. The chlorobenzene layer was filtered and concentrated in vacuo. The residue, comprising 2,2-bistfi-dimethylaminoisopropyimercapto) 4,4 bis fl dimethylaminoisopropoxy) -6,6 -bibenzothiazole, was dissolved in methanol and diluted with acetone. To the resulting solution were added 50 cc. of 25% methanol-hydrogen chloride solution. The 2,2-bis(5- dimethylaminoisopropylmercapto) -4,4 -bis fl-di methylaminoisopropoxy) 6,6 bibenzothiazole tetrahydrochloride was obtained as a slightly 'crearrvcolored precipitate. It was recrystallized from ethanol-acetone, P. 238 C The tetrahydrochloridewas very'soluble in waten'an'd soluble in'ethanol, methanol, and-isop'ropandl.

I claim:

1. A "process "which comprises hydrolyzing 2,2 bis(mercapto) 4,4'---his(rnethcnry') 6; 6"-"bibenz othia'zdle to "form 2,2" bis'fmeroapto') l;4' bisfhydroiiyr fifi bibeiizothiazole, and reacting the latter compound in the form '0'! an alkali metal salt with a lower *dialkylamino'alkyl halide to capto) 4,4 -bis (b -'di-lower alkylaminoalkoxyr- 'thiazole's'odium salt with i-diethylamino-Z c'hloro-ethane. p 4. Aprocesswhichcomprisesreacting 2,2-bis- (merca'pto) 4,4 -hisfihydro'xy) 616' bibenzo- 'thiazole sodium salt with '1-dimethyla'mino 2- 'chloro-ethane.

5. A process whichcomprises reacting 2,2-'bis- (mercap'tm 434' bisthydroxy) 6,6 -bibenzo- 'thiazole sodium salt with l dimethylamino zchloro-propane.

'6. Acompoiind selected from'the group consisting of 2,2-bi's(di-'lower 'alkylanriinoalkylmercapbibenzothiazoles and the acid addition salts thereof 7. 2,2-bis(p-diethylaminoethylmercapto) -4,4'- bis( a-diethylaminoethoxy) 6,6-bibenzothiazo1e.

8. 2,2'-b1's (,8-diethylaminoethylmercapto) -4,4- bis( 8 diethylaminoethoxy) 6,6 bibenzothiazole' tetrahydrochloride.

5 9. 2,2'-bis 13-diethylaminoethylmercapto) -4,4'-

bis(fl diethylaminoethoxy) 6,6 bibenzothiazole lactate.

10. 2,2'-bis (pi-dimethylaminomethylmercapto) 4,4'- (,3 dimethylaminoethoxy) -6,6'-bibenzothia zole.

6 11. 2,2'-bis( 9-dimethylaminoisopropylmercapto) 4,4 bis(,9 dimethylaminoisopropoxy) 6,6-bibenzothiazo1e.

NORBERT STEIGER.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date Heiz Mar. 1, 1932 

1. A PROCESS WHICH COMPRISES HYDROLYZING 2,2''BIS(MERCAPTO -4,4-'' - BIS(METHOXY) -6,6'' - BIBENZOTHIAZOLE TO FORM 2,2''-BIS(MERCAPTO) -4,4''-BIS(HYDROXY) -6,6''-BIBENZOTHIAZOLE, AND REACTING THE LATTER COMPOUND IN THE FORM OF AN ALKALI METAL SALT WITH A LOWER DIALKYLAMINOALKYL HALIDE TO PRODUCE A 2,2''-BIS(DI-LOWER ALKYLAMINOALKYLMERCEPTO) -4,4''-BIS(B-DI-LOWER ALKYLAMINOALKOXY) 6,6''-BIBENZOTHIAZOLE. 